Biological function in the twilight zone of sequence conservation

Abstract Strong DNA conservation among divergent species is an indicator of enduring functionality. With weaker sequence conservation we enter a vast ‘twilight zone’ in which sequence subject to transient or lower constraint cannot be distinguished easily from neutrally evolving, non-functional sequence. Twilight zone functional sequence is illuminated instead by principles of selective constraint and positive selection using genomic data acquired from within a species’ population. Application of these principles reveals that despite being biochemically active, most twilight zone sequence is not functional

Understanding allergic multimorbidity within the non-eosinophilic interactome

Background: The mechanisms explaining multimorbidity between asthma, dermatitis and rhinitis (allergic multimorbidity) are not well known. We investigated these mechanisms and their specificity in distinct cell types by means of an interactome-based analysis of expression data. Methods: Genes associated to the diseases were identified using data mining approaches, and their multimorbidity mechanisms in distinct cell types were characterized by means of an in silico analysis of the topology of the human interactome. Results: We characterized specific pathomechanisms for multimorbidities between asthma, dermatitis and rhinitis for distinct emergent non-eosinophilic cell types. We observed differential roles for cytokine signaling, TLR-mediated signaling and metabolic pathways for multimorbidities across distinct cell types. Furthermore, we also identified individual genes potentially associated to multimorbidity mechanisms. Conclusions: Our results support the existence of differentiated multimorbidity mechanisms between asthma, dermatitis and rhinitis at cell type level, as well as mechanisms common to distinct cell types. These results will help understanding the biology underlying allergic multimorbidity, assisting in the design of new clinical studies.This work was supported by Mechanisms of the Development of ALLergy (MeDALL), a collaborative project done within the EU under the Health Cooperation Work Programme of the Seventh Framework programme (grant agreement number 261357). EM is supported by grants from the European Research Council (n° 757919) and the Swedish Research Council. NL is a recipient of a postdoctoral fellowship from the French National Research Agency in the framework of the "Investissements d’avenir" program (ANR-15-IDEX-02). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 6AM Data Mining provided support in the form of a salary for DA, but did not have any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section